Inactivation of genes that regulate cell proliferation and death is a critical part of the neoplastic process. Crucial genes like tumor suppressor genes can be inactivated via gene deletion, point mutation, or inhibition of transcription. Transcriptional silencing through epigenetic mechanisms is associated with acquisition of promoter methylation and changes in chromatin structure through histone modification leading to a repressive chromatin state. Attempts to relieve this transcriptional repression have led to consideration of clinical trials using inhibitors of DMA methyltransferases (DNMT) and histone deacetylases (HDAC) in cancer. Our previous studies suggest that DNMT or HDAC inhibitors or the combination can reactivate expression of several epigenetically silenced genes in breast cancer, including the estrogen receptor alpha (ER) in human breast cancer cells. This proposal will build on these observations and the recent availability of agents that can be administered clinically to address the hypothesis that targeting epigenetic mechanisms with a single agent or combination approaches will be an effective strategy for breast cancer treatment through three specific aims: Specific Aim 1) Complete a clinical trial to determine the biological effects of an oral HDAC inhibitor, SAHA, in women who are undergoing primary surgery for breast cancer; Specific Aim 2) Optimize dose and schedule of potential combination therapies in cell culture and xenograft models using clinically relevant agents, and Specific Aim 3) Use the findings from the preoperative clinical trial of SAHA in Specific Aim 1 and the preclinical models in Specific Aim 2 to design a rational trial of combination therapy for women with breast cancer. Because of compelling preclinical data that HDAC inhibitors reactivate expression of ER in ER-negative human breast cancer cell lines and thereby sensitize these cells to growth inhibition by tamoxifen, the primary focus will be on a strategy of tamoxifen and HDAC inhibitor. The studies in this renewal application will continue to enhance our understanding of epigenetic mechanisms as potential therapeutic targets, establish the biological activity of one HDAC inhibitor in women with breast cancer, and lay the foundation for rational clinical trials.